Osilodrostat, a potent oral 11β-hydroxylase inhibitor:
22-week, prospective, Phase II study in Cushing’s disease
Maria Fleseriu MD, Rosario Pivonello MD, Jacques Young MD,
Amir H Hamrahian MD, Mark E Molitch MD, Chikara Shimizu MD,
Tomoaki Tanaka MD, Akira Shimatsu MD, Tracy White MSc, Annie Hilliard PhD,
Chuan Tian PhD, Nicholas Sauter MD, Beverly MK Biller MD, Xavier Bertagna MD
Supplementary Appendix
Methods
Outcomes
Pharmacodynamic parameters were analyzed at one of two central laboratories (Quest Diagnostics,
Hounslow, UK or Quotient, Fordham, UK) and were assessed using liquid chromatography–tandem
mass spectrometry (LC-MS/MS; serum cortisol, salivary cortisol, 11-deoxycortisol, 11deoxycorticosterone, aldosterone), radioimmunoassay (renin), or chemiluminescent immunoassay
(ACTH). Of the parameters measured, Quest Diagnostics analyzed: UFC, cortisol, ACTH, 11deoxycortisol, aldosterone, renin, total testosterone, luteinizing hormone (LH), follicle-stimulating
hormone
(FSH),
estradiol,
and
HbA1c.
Quotient
analyzed:
UFC,
salivary
cortisol,
11-deoxycorticosterone, potassium, and sodium. The primary endpoint is based on the UFC
measurements assessed at Quest Diagnostics.
Safety and tolerability were assessed based on the monitoring and recording of all adverse events
(AEs) throughout the study. AEs were defined using terminology in the Medical Dictionary for
Regulatory Activities (MedDRA; version 13.1), and severity was graded according to the National
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Cancer Institute Common Toxicity Criteria version 4.03. Various clinical and laboratory parameters,
such as blood pressure, weight, fasting plasma glucose, HbA1c, and fasting lipid levels, were assessed
after 10 and 22 weeks of treatment. Other safety assessments included: physical examination (for
clinical signs of hyper- or hypocortisolism and possible AEs related to osilodrostat); safety
electrocardiograms 1.5 hours post-dose (for QTcF prolongation) at each visit; MRI scan of pituitary
with contrast (for evidence of possible corticotroph tumor progression) at screening/baseline and
week 22; electrolytes, blood urea nitrogen, creatinine, liver function tests, hematology, biochemistry,
and urinalysis at each visit (for general safety, hypokalemia, or hyperkalemia); serum or urine
pregnancy test (women only) at each visit.
Results
Patient population
Two patients discontinued prematurely from the study. One patient (expansion cohort) discontinued at
week 2 because of an AE (grade 3 papular rash); muscular weakness, nausea, and diarrhea were also
reported. UFC levels had decreased rapidly from 205 to 54 nmol/24h during the week prior to
discontinuation. The other patient (expansion cohort) discontinued at week 6 because of a nontreatment-related administrative issue. This patient did not report any symptomatic AEs and had UFC
levels within the normal range at discontinuation. Although both patients who discontinued had UFC
<ULN, they are classified as non-responders because they were not in the study at weeks 10 or 22.
Response to osilodrostat
Partial responders and non-responders
Two patients classified as non-responders at week 22 were responders at week 10. The first of these
was the patient hospitalized for a serious AE of polyuria/polydipsia with uncontrolled Cushing’s
disease during week 14. This patient had been classified as a partial responder at week 10 since UFC
levels had decreased by >50% from baseline. Osilodrostat dose was titrated to 20 mg/day at week 2
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and the patient had a normal UFC at week 8 on that dose. Dose was subsequently reduced at week 8
to 10 mg in the morning and 5 mg in the evening (owing to loss of appetite, asthenia, headache, and
nausea); there were no further dose changes to week 22, and all UFC values between week 8 and
week 22 were >ULN. Thus, although a dose of 20 mg/day resulted in control, a dose reduction to
15 mg/day was performed because of AEs and UFC levels were no longer controlled on the lower
dose. The second patient had UFC levels <ULN at weeks 6, 10, and 18, but not at week 14 or 22,
based on analyses at the central laboratory. However, based on analyses at the local laboratory, UFC
levels were <ULN at weeks 6, 10, 14, 18, and 22. As such, there was a discrepancy between the
laboratory values at week 14. As the local laboratory value, which was being used for the purpose of
dose adjustments, was normal at week 14, the dose was not increased. Osilodrostat dose was titrated
to 10 mg/day at week 2 and this dose was unchanged until week 22.
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Effect of osilodrostat on other hormone levels
Supplementary Table 1. ACTH and adrenal hormones during osilodrostat treatment (safety analysis set)
Follow-up cohort
Expansion cohort
All patients
Baseline
Week 10
Week 22
Baseline
Week 10
Week 22
Baseline
Week 10
Week 22
19.8 ± 9.8
29.8 ± 26.0
39.3 ± 22.5
20.4 ± 9.8
51.5 ± 65.5
95.0 ± 161.1
20.2 ± 9.5
46.1 ± 58.1
81.1 ± 140.6
(12–34)
(5–59)
(16–60)
(6–43)
(11–246)
(16–581)
(6–43)
(5–246)
(16–581)
5.5 ± 6.5
58.5 ± 68.9
60.2 ± 59.2
4.2 ± 4.6
59.3 ± 56.6
49.9 ± 47.9
4.5 ± 4.9
59.1 ± 57.4
52.4 ± 49.1
(1.3–15.2)
(5.1–158.0)
(8.4–145.5)
(0–19.1)
(4.8–179.1)
(7.0–168.3)
(0–19.1)
(4.8–179.1)
(7.0–168.3)
11-deoxycortico-
0.2 ± 0.1
4.4 ± 3.8
3.9 ± 2.8
0.3 ± 0.4
8.3 ± 9.6
7.3 ± 10.0
0.3 ± 0.3
7.2 ± 8.4
6.3 ± 8.6
sterone, nmol/L
(0.1–0.3)
(0.3–9.0)
(0.7–6.7)
(0.1–1.4)
(0.9–26.0)
(1.0–26.1)
(0.1–1.4)
(0.3–26.0)
(0.7–26.1)
16.5 ± 33.0
62.5 ± 125.0
52.2 ± 76.8
34.8 ± 47.9
43.3 ± 69.3
41.7 ± 70.4
(0–284)
(0–250)
ACTH, pmol/L
11-deoxycortisol,
nmol/L
Aldosterone,
pmol/L
127.0 ±
165.5 ±
177.0
255.1
(0–66)
(0–250)
(0–388)
Renin, mU/L
156.9 ±
235.7
(0–284)
(0–133)
(0–927)
(0–927)
74.0 ± 102.3
54.5 ± 93.2
57.1 ± 98.2
23.7 ± 18.1
59.6 ± 149.8
66.6 ± 148.7
34.9 ± 50.6
58.3 ± 134.9
64.2 ± 134.8
(6–224)
(4–194)
(0–204)
(3–68)
(0–533)
(3–533)
(3–224)
(0–533)
(0–533)
All data are mean ± SD (range). Normal ranges are as follows: ACTH, 1.8–9.2 pmol/L; 11-deoxycortisol, 0–3.92 nmol/L, 11-deoxycorticosterone,
0.12–0.35 nmol/L (males) and 0.05–0.39 nmol/L (females); renin, not available; aldosterone, 55–250 pmol/L. SD, standard deviation
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Supplementary Figure 1. Absolute change in ACTH from baseline in the 17 patients who
completed 22 weeks (safety analysis set)
600
Baseline
200
Week 22
180
160
Expansion cohort
Follow-up cohort
ACTH (pmol/L)
140
120
100
80
60
40
20
Normal
range
0
Patients
Note: Individual patient data are shown in the same order as in Figure 1 in the manuscript. Normal range: 1.1–
11.1 pmol/L
The observed increase in mean ACTH levels was primarily driven by two patients. In one patient,
who originally presented with an aggressive tumor with invasion of the left cavernous sinus at
diagnosis that was treated with surgery and radiation, ACTH levels reached 581 pmol/L at week 22
and a peak of 1084 pmol/L at week 26 at an osilodrostat dose of 60 mg/day. Tumor size was not
evaluable at baseline and week 22. In a second patient, the initial osilodrostat dose of 10 mg/day was
stable from day 1 to week 22, and UFC values were <ULN at all occasions from weeks 2 to 22.
ACTH levels increased from 6 pmol/L at baseline to 243 pmol/L at week 18, 196 pmol/L at week 22
and 231 pmol/L at week 26. The greatest tumor diameter increased from 3.3 to 5.0 mm (change 1.7
mm) from baseline to week 22. Tumor volume increased from 13.7 mm3 at baseline to 17.5 mm3 at
week 22, representing a 28% increase. The patient did not experience any symptoms of compression
of the optic chiasm from the tumor, or any symptoms to suggest adrenal insufficiency, except for
fatigue.
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Supplementary Figure 2. Individual changes in testosterone levels during treatment (safety
analysis set)
Males
Females
30
Testosterone (nmol/L)
25
Normal range
(males)
20
15
10
5
0
Baseline
Normal range
(females)
Week 10
Week 22
Note: Each line represents an individual patient. Normal ranges are as follows: males, 8.7–38.2 nmol/L;
females, 0.1–1.6 nmol/L
Estradiol, LH, and serum FSH levels in women were, in most cases, within the normal range;
however, since data on the stage of the menstrual cycle and menopausal status were not collected,
interpretation of these results is limited. In the five male patients, serum estradiol levels showed mild
and transient increases above the normal range. In men, serum LH and FSH levels slightly decreased
from baseline to week 22 (Supplementary Table 2). In females, there was a four-fold increase in LH
and a 2.4-fold increase in FSH from baseline to week 22.
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Supplementary Table 2. LH and FSH values at baseline and week 22, by gender
All patients
LH, U/L
FSH, U/L
Baseline
Week 22
Change
Male
3.2 ± 1.9
2.4 ± 1.8
–0.8 ± 2.9
Female
2.4 ± 2.1
9.9 ± 17.0
7.8 ± 15.7
Male
5.9 ± 2.8
3.9 ± 2.9
–2.0 ± 2.2
Female
7.6 ± 11.9
18.9 ± 37.1
11.3 ± 24.1
All data are mean ± SD. Normal ranges are as follows: LH males, 1.5–34.6 U/L; LH females,
0.5–76.3 U/L, depending on the stage of the menstrual cycle and menopausal status; FSH males, 1.6–8.0 U/L;
FSH females, 1.5–116.3 U/L, depending on the stage of the menstrual cycle and menopausal status. Note:
Information on the menstrual cycle and menopausal status was not collected
Changes in pituitary tumor size
Supplementary Table 3. Pituitary tumor size (longest diameter) in evaluablea patients at
baseline and week 22 (safety analysis set)
Baseline diameter,b
Week 22 diameter,b
Change in diameter,
mm
mm
mm
28/female
3.3
5.0
+1.7
51/female
6.9
6.9
0
43/female
5.0
4.0
–1.0
35/female
10.0
9.0
–1.0
39/female
7.0
6.0
–1.0
29/male
3.5
5.0
+1.5
Age (years)/sex
a
Measurable tumor diameter at both baseline and week 22. bDefined as the longest measurable diameter
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Safety and tolerability of osilodrostat
Three serious AEs were reported in two patients. One patient had two serious AEs reported
concurrently at week 34: gastroenteritis and QT prolongation. The QT prolongation was noted when
the patient was hospitalized for gastroenteritis with dehydration; it did not reappear when treatment
was resumed. Another patient was hospitalized during week 14 for polyuria and polydipsia, most
likely related to diabetes insipidus, with uncontrolled Cushing’s disease (UFC levels increased from
within the normal range [57 nmol/24h] at week 8 to 389 nmol/24h at the time of hospitalization and
527 nmol/24h at week 22). Osilodrostat dose changes in this patient are already described on page 3
of the Supplementary Appendix.
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Supplementary Table 4. Details on patients with adrenal insufficiency reported as an AE
Pt
Day AE
Duration of
UFC when
Morning serum
reported
AE, days
AE first
cortisol when
reported,
AE first
nmol/24h
reported,
Other
Osilodrostat
GC
symptoms
dose changes
replacement
reported
Notes
therapy
nmol/L
1
2
18 and 51
180
3 and 9,
116 and 31,
196 and 232,
respectively
respectively
respectively
(WNR)
(WNR)
11
10 (<LLN)
119 (<LLN)
Fatigue
Interrupted for
None
Vital signs normal and no
1–2 days on
hypotension. Potassium was
three
3.3 mmol/L (normal range:
occasions.
3.4–4.8 nmol/L) on day 56 and
Decreased
was normalized at day 70. Sodium,
from 40 to
calcium and magnesium levels were
10 mg/day
normal on days 14 and 56
Dizziness,
Decreased
None
Vital signs and electrolytes normal.
asthenia,
from 20 to
No hypotension. Hypomagnesemia
depression
10 mg/day
(0.70 mmol/L; normal range 1.8–2.5)
was reported as an AE (day 182)
9
3
57
70
5 (<LLN)
61 (<LLN)
Nausea,
Decreased
tachycardia
from 10 to
(days 58
2 mg/day
None
Vital signs, electrolytes, magnesium,
and calcium normal. No hypotension
and 69,
respectively)
4
5
182
205
60
Unknown
11.7 (WNR)
6.4 (<LLN)
72 (<LLN)
160 (WNR)
None
Decreased
None
From baseline to day 182: SBP
from 60 to
decreased from ~138 to ~100 mmHg;
10 mg/day;
heart rate increased from ~90 to
later
122 bpm. No hypotension.
interrupted for
Electrolytes, magnesium, and
a few weeks
calcium normal
Syncope,
Decreased
None
SBP and DBP decreased from
malaise
from 10 to
~120/83 on day 1 to ~110/60 mmHg
2 mg/day
on day 210. Electrolytes, magnesium,
and calcium normal
6
37
Unknown
3.5 (<LLN)
135 (WNR)
Not reported
Decreased
Dex initiated
Vital signs, electrolytes, magnesium,
from 7 to
on day 56
and calcium normal. No hypotension
10
4 mg/day
Normal ranges are as follows: UFC, 11–138 nmol/24h; morning serum cortisol, 127–567 nmol/L. DBP, diastolic blood pressure; Dex, dexamethasone;
GC, glucocorticoid; Pt, patient; SBP, systolic blood pressure; WNR, within normal range
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